Are You Confident of the Diagnosis?

Hyperhidrosis (HH) may be defined as excessive sweating beyond the volume required for thermoregulation. It may be primary(idiopathic, essential) or secondary to a number of medical conditions or prescribed drugs. HH can be generalized or focal. Generalized HH is beyond the scope of this section which will focus on Primary Focal HH, the most common type of HH. Primary focal HH affects mainly the axillae, hands and feet and less often the face, groins or other parts of the body.

What you should be alert for in the history

The line between physiological sweating and HH is sometimes difficult to draw. However, visible, excessive sweating of at least 6 months duration without apparent cause with at least two of the following characteristics should help to establish the diagnosis of primary focal HH:

Bilateral and relatively symmetric

Impairs daily activities

Frequency of at least one episode per week

Age of onset less than 25 years

Positive family history

Cessation of focal sweating during sleep

Axillary HH can cause staining and damaging of clothes. Palmar HH sufferers are not able to handle paper without soaking it. They are embarrassed during hand shaking at a social encounter or a job interview. Due to the corrosive action of their sweat, they may even be denied access to certain jobs, such as those in the electronic industry. Palmar HH is often associated with plantar HH, another awkward condition which may be complicated with bromhidrosis, tinea pedis and many other skin disorders. Wearing away of socks and shoes at an accelerated rate is another unpleasant consequence of plantar HH.

Regardless of the affected area: axillae, hands or feet, primary focal HH almost always causes significant social embarrassment and can lead to social stigmatization and discrimination. Those affected with craniofacial HH may suffer greatly from being confronted in public: they have to wipe their face very frequently because of the dripping of sweat into their eyes. Caffeine, and emotional, mental or physical activity may trigger or aggravate craniofacial HH.

Characteristic findings on physical examination

Figure 1.

Palmar hyperhidrosis. (Courtesy of Bryan Anderson, MD)

Expected results of diagnostic studies

Tests quantifying sweat production are not generally required in routine clinical practice. They are mostly performed during clinical trials. Minor’s iodine starch test is useful in delineating the hyperactive eccrine glands prior to injection with botulinum toxin or surgery of axillary sweat glands.

Diagnosis confirmation

The Hyperhidrosis Disease Severity Score (HDSS) (Table I) is a tool designed to help the practitioner to quickly determine the level of interference with daily activities caused by HH in a given patient.

Table I.

Hyperhydrosis disease severity scale (HDSS)

Class I

My sweating is never noticeable and never interferes with my daily activities

Who is at Risk for Developing this Disease?

In the United States, hyperhidrosis (HH) affects roughly 2.8% of the population. The age group most affected ranges between 18 and 30 years. Axillary HH affects 50.8% of individuals with primary focal HH or about 1.4% of the US population. Up to 50% of the patients report a positive family history.

What is the Cause of the Disease?

Etiology

Causes of HH include genetic, metabolic, hormonal or idiopathic pathology,as well as a long list of medications that trigger HH among them: tricyclic antidepressants, cholinbergics, antidiabetics, antipyretics, particularly naproxen and aspirin. Alcohol and opiates are other triggering factors for HH, together with hot beverages and spicy foods.

Pathophysiology

The pathophysiology of primary focal HH is poorly understood but is believed to be associated with overactivity of the sympathetic nervous system.

AC = aluminum chloride hexahydrate
SA = salicylic acid
* The concentration of SA in the gel is 4% unless specified otherwise
† Iontophoresis is performed with tap water to which 1 -2 mg of glycopyrrolate could be added in each tray to enhance its drying effect.
BTX-A = Botulinum Toxin Type A (Botox® Allergan)

A. BTX-A injections 200 units on forehead and scalp.
B. BTX-A injections 200 units on forehead and scalp + 30 % AC / in SA gel + an anticholinergic** such as :
a. Oxybutynin Hydrochloride (Ditropan) 5mg three times a day as necessary
b. Glycopyrrolate (Robinul,Avert) 1 to 2 mg three times a day as necessary
c. Propantheline (Pro-Banthine) 7.5 mg three times a day
C. Endoscopic Transthoracic Sympathectomy.

One of the main criteria for determining whether treatment is justified is the impact of HH on the patient’s quality of life. The goal of therapy is to design a step-by-step approach for each patient taking into account: the age of the patient, the area to be treated, the patient’s tolerance to former therapies, and the cost of the treatment modality, including its potential side effects. Aluminum chloride hexahydrate (AC), the most effective of aluminum salts, should be tried first. The efficacy of AC increases with higher concentrations, but, so does its irritancy.

Topical aluminum chloride hexahydrate (AC) formulations at low concentrations (15%) should be tried first and raised up step by step to 20%, 30%, 40% and as high as 55% until sweat control is achieved (cf tables). Failure to respond to topical AC formulations justifies the use of iontophoresis and botulinum toxin type A, Botox® Allergan, (BTX-A) injections respectively. If still no reponse, combination treatments (AC + Iontophoresis + BTX-A) should be tried before resorting to surgery.

Optimal Therapeutic Approach for this Disease

Aluminum chloride hexahydrate

AC is the most effective of aluminum salts and should be tried first in the management of primary focal HH. AC is readily available on the market in concentrations ranging from 6.25 % (Drysol mild) to 20% (Regular Drysol).

The problem with these preparations is that they are dispensed in an alcohol vehicle. While AC is soluble 1-in-1 in water, it is only soluble 1-in-4 in ethanol; for that reason AC cannot be raised to concentrations above 25% in an alcohol vehicle as it becomes fully saturated. On the other hand, AC dispensed in a gel vehicle can reach supersaturated concentrations as high as 55%. Morever, salicylic acid (SA) could be added to the gel vehicle to enhance its antiperspirant effect.

Recently, 15% AC in a 2% SA has been marketed in the US and Canada under the name Hydrosal Gel. Knowledgeable pharmacists are capable of preparing extemporaneous formulations, ranging from 15% to 55% aluminum chloride in a hydroalcoholic gel containing 2-6% salicylic acid tailored to patient’s tolerance and need. AC in SA gel offers the following advantages in the treatment of primary focal HH, especially in resistant cases.

--It may be used as a first-line therapy for palmar and plantar hyperhidrosis because alcohol gel is better tolerated than an alcohol solution. The rationale of using SA in the gel vehicle is to enhance the penetration of AC through the thick horny layer present on the palms and soles and, having antiperspirant properties of its own, SA could act synergistically with AC to enhance its antiperspirant effect. In this extemporaneous gel vehicle, AC is dispersed in the form of microcrystals, and for that reason it can reach supersaturated concentrations of up to 55%.

--It may be used as adjunct treatment to iontophoresis when iontophoresis alone fails to control HH.

--It may be used as an adjunct treatment to Botulinum toxin type A (BTX-A) when BTX-A alone fails to show any improvement of palmar or plantar HH, a month after its injection.

--It may be used to extend the interval between BTX-A injections, especially when the effect of BTX-A starts to fade. High doses of BTX-A (above 300 units), coupled with shorter intervals between injections have the potential of inducing neutralizing antibodies which render BTX-A injections totally ineffective.

Anticholinergic agents

Unfortunately, the adverse effects caused by this group of drugs (eg, oxybutynin [Ditropan], propantheline [Pro-Banthine]) may be worse than the sweating itself. These effects include: tachycardia, dry mouth, decreased intestinal motility, urinary retention and aggravation of certain conditions such as glaucoma). Furthermore, these effects sometimes appear even before the sweating problem is controlled. Although these drugs have little place in the treatment of focal HH, some patients may benefit from them.

Iontophoresis

Iontophresis used with tap water is another way to effectively control HH, presumably by producing a physical blockage of the sweat ducts at the level of the stratum corneum. This method is most useful for palmar and plantar HH and less recommended for axillary HH because of burning and stinging. The addition of an anticholinergic like glycopyrrolate 1-2g/day further enhances the drying effect of iontophoresis. One of the disadvantages of iontophoresis is that it is a time-consuming procedure and therefore it is not readily accepted. Detailed instructions are provided by the manufacturers of these devices.

Botulinum Toxin Type A

BTX-A has revolutionized the treatment of HH. However, pain during the injection of BTX-A into the palms and soles, and muscle weakness particularly on the hands, may deter its use in the treatment of palmar and plantar HH.

Pain during the injections of BTX-A on the palms and soles.

While these injections are performed for axillary HH, with little or no anesthesia, some form of anesthesia is needed for palmar and plantar HH in order to be able to inject BTX-A into the densely innervated skin of the palms or soles. Nerve block and Bier’s block (Bier’s block or intravenous regional anesthesia generally involves the introduction of a a local anesthetic into a vein on the dorsum of the hand to block its nerve supply in order to be able to inject BTX-A painlessly with needle) are amongst the most effective methods of anesthesia. Most physicians are unable or unwilling to perform reliable nerve blocks, and many patients will not accept a nerve block.

Bier’s block, in experienced hands, is considered an excellent way to provide anesthesia, but systemic effects could result from the sudden release of anesthetic into systemic circulation. An alternative method is anesthesia with an appropriate needle-free injector. In the author’s experience, needle-free anesthesia prior to injection of BTX-A with needle is a safe and practical way to overcome the pain during BTX-A injection of the palms and soles. Many patients who experienced the nerve block in the past, prefer by far the needle-free anesthesia and have come back to receive a 7th or 8th treatment since 2004.

The Med-Jet® is the needle free device used by the author because it has an adjustable volume per spurt (0.03 to 0.3 mL) and an adjustable pressure (130 to 300 psi). It goes without saying that like any new medical procedure, it is associated with a learning curve. Inappropriate use of the device can cause bruising and crusting that can persist for weeks. (For more details on the use of the Med-Jet see the segment on how to deal with the needle-phobic patient)

Muscle weakness occurring on the hands

Prevalence and importance of hand or finger weakness vary according to doses of BTX-A injected and to how weakness is defined and measured. Weakness is self-limited and reversible, lasting between 2 to 3 weeks. Subepidermal injection of BTX-A is preferred to the subcutaneous injection in order to avoid functional reduction of manual dexterity.

If all the above measures fail, surgery should be considered with great caution. Removal of the eccrine glands in the axillae may result in disfiguring scars while thoracic or lumbar sympathectomy for palmar and plantar HH respectively may result sometimes in debilitating compensatory HH.

Patient Management

Treatment of primary focal HH is initiated with nightly topical AC preparations (Tables II-IV) at low concentrations and gradually increased, as needed, until control of HH is achieved. Once under control, the treatment frequency is lowered to once or twice a week or even less. Not uncommonly, remission of HH may occur down the road after months or years. If the topical approach fails, iontophoresis could be added to topical therapy, alone or with the addition of anticholinergics (1-2mg glycopyrrolate) dissolved in the tap water of each tray of the iontophoresis device.

If both topicals and iontophoresis fail, BTX-A injections should be considered. BTX-A injections are highly effective for axillary HH, where their rate of success is close to 90%. The rate of success is 75% for palmar HH and only 50% for plantar HH. Patients should be warned about possible muscle weakness in case of palmar HH.

Injections have to be repeated periodically when the effect of BTX-A wears off. The injection-free interval may vary from 6 to 12 months for axillary HH, from 4 to 12 months for palmar HH, and is not well known for plantar HH. Supersaturated concentrations of AC, iontophoresis and BTX-A injections, coul be used in association for recalcitrant plantar cases before resorting to surgery.

The “step up approach” cited in the tables, besides offering the optimal treatment option for each individual, also evaluates the severity of HH more objectively, and, together with the HDSS they favor the approval of insurance companies to cover the expenses for iontophoresis devices or BTX-A injections.

Unusual Clinical Scenarios to Consider in Patient Management

How to manage a case of recalcitrant axillary HH associated with palmar and plantar HH unresponsive to topical preparations of AC and iontophoresis? BTX-A injections are indicated in such a patient, but the area to be injected first may be debatable. This particular patient needs at least a standard dose of 100 units for axillary HH, 200 units for palmar HH and 300 for plantar HH, which amounts to a total dose of 600 units. There is a concern about antibody formation by using such a high dose, although the author never encountered such a complication during the 7 years in which over 1500 patients were treated with BTX-A for primary focal HH.

In the author’s experience, treatment should start on the hands, using the standard dose of 100 units per palm of BTX-A. Injection of the hands alone, has a 40% chance of reducing axillary and plantar HH without further treatment. Palmar HH is the most disabling condition compared to axillary and plantar HH because it cannot be concealed during a hand shake. Control of palmar HH is accompanied by a dramatic improvement in the quality of life of the patient and a marked reduction in the amount of stress which in its turn diminishes sweat on the other areas involved. The amount of sweat reduction could vary greatly from case to case, but it is interesting to note that topical AC and or iontophoresis that failed to control palmar or plantar HH before BTX-A injections, have now a better chance to act after BTX-A injections.

As for the axillary HH, if it remains unchanged, a dose of 50 units of BTX-A per axilla is indicated. Here also, topical AC, if need be, has a better chance to be effective after the BTX-A injections of the axillae. The last step should be the injection of the feet after explaining to the patient the potential risk of antibody development. Fortunately, as mentioned before, antibody formation to BTX-A is not a frequent occurrence.

How to deal with the needle-phobic patient who needs BTX-A injections on the hands or feet? BTX-A could be directly delivered in the needle-phobic through an appropriate needle-free injector, but there may be a 30% loss of its efficacy due splashing and partial denaturing of BTX-A by the violent agitation during the pressurized injection. The Dermojet has been used in the past for the treatment of palmar hyperhidrosis, but the risk of injury to the nerves and vessels being high, due to their superficial localization, it is not a recommended option. This disadvantage does not apply for plantar HH where nerves and vessels are located deeper in the skin and where Dermojet can be used safely. The Dermojet has a fixed volume of 0.1 mL per spurt and a high fixed pressure (above 300 psi).

Needle-free injectors with adjustable volumes and pressure would be more appropriate to use for palmar injection of BTX-A. BTX-A could be delivered directly through the needle-free injector to the subepidermal skin but, as mentioned earlier, partial loss of its efficacy should be considered. The needle-free injector is preferably used to provide anesthesia. In fact, the injection of a tiny volume of 0.03 mL of 2% lidocaine subepidermally with the minimal possible pressure, 140 psi, creates a subepidermal anesthetic wheal through which BTX-A could be injected with a needle, totally free of pain. The fact that the pressure is gradually increased until a wheal has appeared guarantees that the injectate remains superficial, away from the delicate vessel and nerve structures underlying the skin.

The CO2 powered Med-Jet features an adjustable volume and an adjustable pressure. A volume of 0.03 mL (range 0.02 – 0.3 mL) and a pressure of 140 psi (range 130 – 300 psi) are safe parameters to use in the treatment of palmar HH with BTX-A directly into the skin or after needle free anesthesia with lidocaine. Larger volumes and higher pressures lead the injectate to deeper levels and may cause damage to nerve and vessel structures. The author has used the Med-Jet to treat palmoplantar HH in over 250 cases.

The line between physiological sweating and HH is sometimes difficult to draw. Many people affected with this disease are unaware that treatments are available. Therapeutic options vary according to the age of the patient, the area involved, the severity of the disease and the patient’s own tolerance to previous medications. The step up approach should assist the clinician and the patient to chose the optimal therapeutic option at a minimal possible cost and risk. Surgery should be used as a last resort only.

(The line between physiological sweating and HH is sometimes difficult to draw. However, visible, excessive sweating of at least six months duration without apparent cause with at least two of the following characteristics should help to establish the diagnosis of primary focal HH: bilateral and relatively symmetric, impairs daily activities, frequency of at least one episode per week, age of onset less than 25 years, positive family history and cessation of sweating during sleep.)

(Knowledgeable pharmacists are capable of preparing extemporaneous formulations, ranging from 15 to 55% AC in a hydroalcoholic gel containing 2-6% SA tailored to the patient’s need. Keralyt may be used as a vehicle.)

(AC in SA gel offers many advantages in the treatment of focal HH, especially in resistant cases. It may be used as an adjunct treatment to iontophoresis when iontophoresis alone fails to control HH, it may be used as an adjunct treatment to BTX-A when this treatment fails to show any improvement of palmar HH, a month after BTX-A injection.)

(BTX-A has revolutionized the treatment of HH. However, pain during injection of TX-A into the palms or soles and muscle weakness particularly on the hands, may deter its use in the treatment of palmar and plantar HH.)

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